DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1, 6, 9-10, 12, 20, 39, and 41-44 are currently pending.
No claims have been amended.
Claims 10 and 12 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 2-5, 7-8, 11, 13-19, 21-38, 40, and 45-47 remain cancelled.
Claims 1, 6, 9, 20, and 39, and 41-44 have been considered on the merits.
Maintained Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 6, 9, 20, and 39, and 41-44 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an in vitro method of modulating gut cell inflammation in an cell or organoid, comprising contacting a population of intestinal cells from a subject suffering from an inflammatory bowel disease in vitro with a modulating agent in an amount sufficient to modify adherens junctional integrity by altering cytohesion protein degradation and ARF6 GTPase activation in the cell population as compared to the population of interstitial cells in the absence of the modulating agent, wherein the modulating agent modulates C1orf106 and cytohesion ubiquitination, the specification does not reasonably provide enablement for a method of modulating gut inflammation caused by inflammatory bowel disease within a subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims broadly encompass a method of modulating gut inflammation caused by inflammatory bowel disease in any subject, comprising contacting a population of interstitial cells of a subject suffering from an inflammatory bowel disease with a modulating agent in an amount sufficient to modify adherens junctional integrity by altering cytohesion protein degradation and ARF6 GTPase activation in the cell population as compared to the population of interstitial cells in the absence of the modulating agent, wherein the modulating agent modulates C1orf106 and cytohesion ubiquitination. Thus, the claims taken together with the specification imply that the instant method can modulate gut inflammation of any subject, including humans, suffering from inflammation caused by an inflammatory bowel disease.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The claims embody a method of modulating gut inflammation caused by inflammatory bowel disease in any subject, which renders the claims unpredictable.
The method is found to be unpredictable with regards to its ability to modulate gut inflammation caused by an inflammatory bowel disease in any subject.
Firstly, the specification only provides support for modulation of C1orf106 in in vitro cell models as seen in Example 1. The specification does employ a mouse model; however the model is a double knockout of C1orf106 which is used for the expressed purpose of “understand[ing] how C1orf106-mediated degradation of cytohesion-1 alters epithelial cell function” ([0516]). This mouse model is not used to perform the method of modulating gut inflammation caused by inflammatory bowel disease, therefore it does not help support the enablement of the method for use in mice. Additionally, the specification does not provide any information as to how one may conduct the method in a mouse, human, or alternative subject.
Horizon Scan (Canadian Journal of Health Technologies, Oct, 2024) teaches about CRISPR technologies for both in vivo and ex vivo gene editing. Horizon scan teaches that “[t]he long term effects of CRISPR-based therapies are currently unknown…[s]everal ethical considerations related to the use of CRISPR-based therapies have been identified, including the implications of off-target gene modifications” (pg. 2, para 4). Horizon Scan teaches that, in particular gene knock-ins are more challenging than gene knockouts because homology directed repair, used in knock-ins, is less common than non-homologous end joining, seen in knock-outs (pg. 3, para 2). These statements support that CRISPR gene editing in vivo remains an unpredictable art. Additionally, Horizon scan teaches about exa-cel/Casgevy, the one and only CRISPR based therapy to receive regulatory approval anywhere internationally. Exa-cel/Casgevy is an Ex vivo gene editing therapy which targets the BC11A gene in blood cells which have been removed from a patient’s body suffering from sickle cell anemia or Beta-thalassemia. This supports that the jump from in vitro cell models to in vivo gene therapy is unpredictable, since the gene editing endeavors as a whole have only returned a single approved method, which is only capable due to the Ex vivo (removal of subject blood cells prior to gene editing) nature of the therapy. Turning to in vivo therapies, Horizon Scan teaches that “[o]ff-target edits are a key risk associated with gene editing. These can occur when the Cas nuclease cuts at unintended genetic sites, which could result in unknown consequences to an individual’s health” (pg. 6, last para). Therefore, Horizon Scan wholistically supports that, without evidence and explicit guidance in the instant specification, one would not be able to use the invention as claimed.
Kaupbayeva et al (Journal of Functional Biomaterials, 2024) teaches a current review in the advances and obstacles in genome editing with CRISPR using AAV, adenovirus (AdVs), and lentiviral particles. Regarding AAV based methods, Kaupbayeva teaches that high doses of these models cause mild toxicity in animal models (section 2.1). Regarding adenovirus models, Kaupbayeva states that many in vitro models have been developed however, “AdVs pose a significant risk due to their high immunogenicity. Previous research has indicated that they provoke robust immune and inflammatory reactions in animal models, limiting their clinical potential” (Section 2.2). Regarding lentiviral particle models, Kaupbayeva teaches “the potential of LV systems for unpredictable incorporation into the host cell genome poses a challenge” (section 2.3). Therefore, Kaupbayeva supports that each delivery method poses its own specific challenges when looking to move from an in vitro model to treatment of subjects, and without guidance the move to in vivo is unpredictable.
Li et al (Biomaterials) teaches that “[t]o date, efficient in vivo delivery of the CRISPR/Cas9 system to the targeted cells remains a challenge. Although viral vectors have been widely used in the delivery of the CRISPR/Cas9 system in vitro and in vivo, their fundamental shortcomings, such as the risk of carcinogenesis, limited insertion size, immune responses and difficulty in large-scale production, severely limit their further applications” (abstract). Therefore, Li is explicitly supporting that the target of specific cells, such as the instant “method of modulation of gut inflammation”, is highly unpredictable in gene editing technologies.
Due to the minimal guidance provided in the instant specification on how one would perform the method of modulation in a subject, and the overwhelming consensus in the art that gene editing technologies remain an area of unpredictability, especially in subjects, the method of gut modulation is not predictable for use in any system other than in vitro cell based models.
(4) The relative skill of those in the art:
The relative skill of those in the art is high.
(5) The amount of direction or guidance presented and (6) the presence or absence of working examples:
The specification details example 1. Example 1 demonstrates lentiviral particle transduction of LS174T and Caco-2 cells. Example 1 also demonstrates a double knockout of C1orf106-/- in mice and WT C1orf106+/+ mice, used to determine the effect on various protein levels in the mice. Example 1 demonstrates freshly isolated intestinal epithelial cells and primary organoid cultured which have loss of C1ord106 function.
(7) The quantity of experimentation necessary:
Considering the state of the art as discussed above and the high unpredictability and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to use the claimed invention within the broad scope as instantly claimed.
It is the examiner’s position that one skilled in the art could not practice the invention commensurate in the breadth of the claims without undue experimentation. Therefore, claim 22 and its dependents are rejected under 35 U.S.C. 112, first paragraph, for a lack of scope of enablement.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 6, 9, 20, 39, and 41-44 are rejected under 35 U.S.C. 103 as being unpatentable over Schwank et al (Cell Stem Cell 13, 653–658, December 5, 2013) as evidenced by Mohanan et al (Science. 2018 Mar 9; 359(6380): 1161–1166.), in view of Levesque et al (Thesis, Montreal University, Dec 2015, included in IDS), as evidenced by Loh et al (Gut Microbes, 2012), all of which are references of record.
With regards to claim 1, Schwank teaches a method of modulating in vitro intestinal cell (gut cell) inflammation, termed functional repair by Schwank, caused by cystic fibrosis (pg. 655, column 1, para 2). The method comprises contacting patient derived intestinal cells in vitro with a modulating agent, CRISPR as required by claims 1 and 6 (abstract, lines 8-11). Further, CRISPR is used to correct the mutated CFTR allele to wild-type, modulating its stability (pg. 655, column 2, lines 7-14). Schwank found that correcting the mutation (F508del) on CFTR increased the integrity of the intestinal cell organoids (Figure 2).
Schwank does not explicitly state that the intestinal cells are C1orf106 expressing cells, however “C1orf106 is highly expressed in the human intestine and intestinal epithelial cell lines” as required by claims 9 and 39 (Mohanan et al pg. 2, line 25) as evidenced by Mohanan et al.
Schwank does not specifically teach the increase in junctional integrity by altering cytohesin protein degradation and ARF6 GTPase activation as required by claims 1 and 20. Schwank does not teach the modulation of the stability of C1orf106 or the *333F variant of C1orf106 or where the modulating agent is a CRISPR system used to restore the *333F variant to wild-type or another variant with increase protein stability as required by claims 6, 20, and 41. Schwank does not teach increasing the junctional integrity of the intestinal epithelial is by contacting the population of intestinal cells with a proteasome inhibitor and/or agent that increases the stability of the C1orf106 protein as required by claim 42. Schwank does not teach wherein the inflammatory bowel disease comprises ulcerative colitis and Crohn’s disease as required by claim 43. Schwank does not teach wherein the colitis is caused by a bacterial or parasitic infection as required by claim 44.
However, Levesque teaches about the C1orf106 protein, and more specifically it’s involvement in inflammatory bowel disease including Crohn’s disease and ulcerative colitis as required by claims 41 and 43 (abstract). Levesque introduces the *333F variant which has significantly reduced the stability of the C1orf106 protein (pg. 64, para 1). Further, Levesque teaches about a sequencing study in which 350 individuals with Crohn’s disease (CD), and 350 control individuals were sequenced and the results found a rare variant, *333F C1orf106, was associated with CD affected individuals (pg. 31, last 2 para). Levesque also states that the C1orf106 stability is affected by the amino acid substitution seen in the *333F variant as compared to the wild type (pg. 54, para 1) and further, “our protein stability test has shown that rare genetic variant of 333F C1orf106 significantly reduces its stability and consequentially its protein level in balance” (pg. 64, para 2). Further, the CRISPR system of Schwank in combination with the modulation target taught by Levesque reads on an agent that increases the stability of the C1orf106 protein as required by claims 20 and 42.
Levesque also teaches that in cells which stably overexpress the *333F variant, only “partial localization with ZO-1, used as a tight junction (TJ) marker” and that tighter adherens junctions (AJ) were observed (abstract). Further, Levesque teaches that the localization of C1orf106 at these regions suggest its possible implication in epithelial barrier homeostasis. Therefore, Levesque supports that the TJ markers are decreased/only partially localized in cells which contain the *333F variant. From this teaching one of ordinary skill in the art would easily extrapolate that reverting the cells to a WT variant would revert the TJs to WT as well (i.e., the claimed “sufficient to modify junctional integrity of the intestinal cell” of claim 1).
Levesque does not specifically teach that the inflammation is caused by a bacterium as required by claim 44, however both “Crohn’s disease and ulcerative colitis are characterized by a depletion of Firmicutes in conjunction with an increase of gram-negative bacteria, namely E. coli” as evidenced by Loh et al (Figure 1).
One of ordinary skill in the art at the effective filing date of the instant invention would find it obvious to combine the method of treating cells in vitro which are known to cause gut inflammation by replacing a known mutated gene with a WT taught by Schwank with the mutated variant of C1orf106, *333F, taught by Levesque to be related to CD and gut inflammation to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Levesque teaches that a sequencing study which 350 individuals with Crohn’s disease (CD) and 350 control individuals were sequenced and the results found a rare variant, *333F C1orf106, was associated with CD affected individuals (pg. 31, last 2 para). Additionally, Levesque states that overall their results support a role in C1orf106 in ITNs (overarching category of diseases including inflammatory bowel disease) and which would place C1orf106 on the list of causal genes for ITNs (pg. 68). One of ordinary skill in the art would have a reasonable expectation of success when combining Schwank with Levesque because Schwank teaches the necessary information to perform the CRISPR based disease treatment in intestinal (gut) cells in vitro by replacing a known mutation with the WT in intestinal cells. Additionally, one of ordinary skill in the art would reasonably expect that restoring the *333F variant to WT by the CRISPR method of Schwank would modulate the stability of the C1orf106 protein by increasing the stability of the protein where the inflammation is caused by Crohn’s disease or ulcerative colitis because Levesque states that the C1orf106 stability is affected by the amino acid substitution seen in the *333F variant as compared to the wild type (pg. 54, para 1) and further, “our protein stability test has shown that rare genetic variant of 333F C1orf106 significantly reduces its stability and consequentially its protein level in balance” (pg. 64, para 2). Therefore, the combined teachings of Schwank teach the method of modulating gut inflammation by correcting a disease-associated variant in vitro (*333F C1orf106) with a WT gene (WT C1orf106) would inherently increase the stability of the C1orf106 protein as required by claim 39.
Therefore, Schwank and Levesque render the claims obvious.
Response to Arguments
Applicant's arguments filed 12/08/2025 have been fully considered but they are not persuasive.
Applicant argues (Remarks, pg. 4, last para), in reference to the 112(a) rejection of record, that the Office action mischaracterizes claim breadth as encompassing “any subject, including humans” because claim 1 recites “contacting a population of intestinal cells of a subject suffering from an inflammatory bowel disease” which limits the claims to “subjects with intestinal cells amenable to the disclosed modulation approach, not any conceivable biological system”. Applicant also states that the mammalian limitation appropriately reflects the scops teachings “which demonstrate the mechanism in human cell lines (Caco-2, LS174T), humans-derived organoids, and mouse knockout models”.
In response, this argument is not found persuasive because the breadth of the term subject remains inclusive of humans, and more broadly, any subject which can suffer from an inflammatory bowel disease. The breadth of the claims encompass any subject suffering from inflammatory bowel disease and do not specify that the subject must be “amenable to the disclosed modulation approach”. Additionally, due to the lack of enablement in the specification it is not clear how a person or ordinary skill in the art would determine if a subject is “amenable to the disclosed modulation approach” without undue experimentation.
Additionally, the specification only provides support for modulation of C1orf106 in in vitro cell models as seen in Example 1. The specification does employ a mouse model; however the model is a double knockout of C1orf106 which is used for the expressed purpose of “understand[ing] how C1orf106-mediated degradation of cytohesion-1 alters epithelial cell function” ([0516]). This mouse model is not used to perform the method of modulating gut inflammation caused by inflammatory bowel disease, therefore it does not help support the enablement of the method for use in mice.
Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 5), in reference to the 112(a) rejection of record, that CRISPR technology had advanced to clinical trials in 2017 and a PHOSITA would recognize CRISPR as clinically viable therapeutic modality. Additionally, that the single CRISPR therapy which achieved regulatory approval in 2024 reflects the “stringent clinical trial requirements, not whether gene editing technology was enabled”. Applicant also argues that a PHOSITA would need only routine experimentation to apply the method using any known delivery method without undue experimentation.
In response, the argument is not found persuasive. Although a PHOSITA may have recognized CRISPR as a therapeutic modality as early as 2017, this does not equate to the claimed invention requiring only routine experimentation for a PHOSITA to make and use. Horizon Scan was relied upon to demonstrate that gene knock-ins are more challenging than gene knockouts because homology directed repair, used in knock-ins, is less common than non-homologous end joining, seen in knock-outs (pg. 3, para 2). These statements support that the currently claimed invention which encompasses CRISPR gene editing in vivo remains an unpredictable art. Additionally, Horizon scan discloses exa-cel/Casgevy, the one and only CRISPR based therapy to receive regulatory approval anywhere internationally. Exa-cel/Casgevy is an Ex vivo gene editing therapy which targets the BC11A gene in blood cells which have been removed from a patient’s body suffering from sickle cell anemia or Beta-thalassemia. This supports that the jump from in vitro cell models to in vivo gene therapy is unpredictable, since the gene editing endeavors as a whole have only returned a single approved method, which is only capable due to the Ex vivo (removal of subject blood cells prior to gene editing) nature of the therapy. Thus, without guidance from the specification a PHOSITA would need undue experimentation regarding performing the method as instantly claimed. The specification does not provide guidance regarding delivery to the relevant tissue/organ, which was a known challenge in the art and not amenable to routine optimization. Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 6, para 2 spanning pg. 7 para 1), in reference to the 112(a) rejection of record, that the working examples of the specification including cell models and primary intestinal organoids provide an art recognized model “that predict[s] in vivo responses, and the specification’s demonstration of successful modulation in these models provides substantial guidance for therapeutic applications.
In response, the argument is not found persuasive. the specification only provides support for modulation of C1orf106 in in vitro cell models as seen in Example 1. The specification does employ a mouse model; however the model is a double knockout of C1orf106 which is used for the expressed purpose of “understand[ing] how C1orf106-mediated degradation of cytohesion-1 alters epithelial cell function” ([0516]). This mouse model is not used to perform the method of modulating gut inflammation caused by inflammatory bowel disease, therefore it does not help support the enablement of the method for use in mice. Additionally, organoids lack key physiological components which limits their ability to model in vivo whole organism response and there has not been any evidence provided that the organoid model of the specification is an art-recognized model for predicting in vivo efficacy of treatments to intestinal cells in patients or subjects in vivo. Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 7 last para spanning pg. 8 para 3), in reference to the art rejection, that the Office action materially misquotes the reference because Levesque’s abstract states “We did observe tighter colocalization with E-cadherin, a canonical marker for adherens junction (AJ), typically located below the TJ complex” and Applicant asserts that “at no point does Levesque actually state that tighter AJs were functionally observed.
In response, the argument is not found persuasive. Applicant’s argument that Levesque has been misrepresented is not found persuasive which is the basis of the arguments. The cited portion of Levesque expressly describes tighter co-localization with E-Cadherin, a canonical adherens junction marker, which would indicate increased integrity of adherens junctions. The claims merely recite “a modulating agent in an amount sufficient to modify adherens junctional integrity”. Therefore, Levesque reads on modifying junctional integrity and the argument is not found persuasive.
Applicant argues (Remarks, pg. 10-11) that the Office action only relies on inherency to bridge the alleged gap of Levesque to teach the modulation of both TJs and AJs. Additionally, Applicant provides description of the specification’s “extensive functional validation” including specific results not present in the claimed limitation of to “modify adherens junctional integrity”.
In response, the argument is not found persuasive. Levesque’s abstract states “We did observe tighter colocalization with E-cadherin, a canonical marker for adherens junction (AJ), typically located below the TJ complex”. Applicant’s argument that Levesque has been misrepresented is not found persuasive which is the basis of the arguments. The cited portion of Levesque expressly describes tighter co-localization with E-Cadherin, a canonical adherens junction marker, which would indicate increased integrity of adherens junctions. The claims merely recite “a modulating agent in an amount sufficient to modify adherens junctional integrity”.
Additionally, In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., greater than 2-fold decrease in surface E-cadherin) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Therefore, Levesque reads on modifying junctional integrity and the argument is not found persuasive.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632